The invention relates to inhibitors of RNA dependent RNA polymerases, particularly those viral polymerases within the Flaviviridae family, and more particularly the NS5B polymerase of HCV.
About 30,000 new cases of hepatitis C virus (HCV) infection are estimated to occur in the United States each year (Kolykhalov, A. A.; Mihalik, K.; Feinstone, S. M.; Rice, C. M.; 2000; J. Virol. 74: 2046-2051*). HCV is not easily cleared by the hosts"" immunological defences; as many as 85% of the people infected with HCV become chronically infected. Many of these persistent infections result in chronic liver disease, including cirrhosis and hepatocellular carcinoma (Hoofnagle, J. H.; 1997; Hepatology 26: 15S-20S*). There are an estimated 170 million HCV carriers world-wide, and HCV-associated end-stage liver disease is now one of the leading cause of liver transplantation. In the United States alone, hepatitis C is responsible for 8,000 to 10,000 deaths annually. Without effective intervention, the number is expected to triple in the next 10 to 20 years. There is no vaccine to prevent HCV infection. Prolonged treatment of chronically infected patients with interferon or interferon and ribavirin is the only currently approved therapy, but it achieves a sustained response in fewer than 50% of cases (Lindsay, K. L.; 1997; Hepatology 26: 71S-77S*, and Reichard, O.; Schvarcz, R.; Weiland, O.; 1997 Hepatology 26: 108S-111S*).
*Incorporated Herein by Reference 
HCV belongs to the family Flaviviridae, genus hepacivirus, which comprises three genera of small enveloped positive-strand RNA viruses (Rice, C. M.; 1996; xe2x80x9cFlaviviridae: the viruses and their replicationxe2x80x9d; pp. 931-960 in Fields Virology; Fields, B. N.; Knipe, D. M.; Howley, P. M. (eds.); Lippincoft-Raven Publishers, Philadelphia Pa.*). The 9.6 kb genome of HCV consists of a long open reading frame (ORF) flanked by 5xe2x80x2 and 3xe2x80x2 non-translated regions (NTR""s). The HCV 5xe2x80x2 NTR is 341 nucleotides in length and functions as an internal ribosome entry site for cap-independent translation initiation (Lemon, S. H.; Honda, M.; 1997; Semin. Virol. 8: 274-288*). The HCV polyprotein is cleaved co- and post-translationally into at least individual polypeptides (Reed, K. E.; Rice, C. M.; 2000; Curr. Top. Microbiol. Immunol. 242: 55-84*). The structural proteins result from signal peptidases in the N-terminal portion of the polyprotein. Two viral proteases mediate downstream cleavages to produce non-structural (NS) proteins that function as components of the HCV RNA replicase. The NS2-3 protease spans the C-terminal half of the NS2 and the N-terminal one-third of NS3 and catalyses cis cleavage of the NS2/3 site. The same portion of NS3 also encodes the catalytic domain of the NS3-4A serine protease that cleaves at four downstream sites. The C-terminal two-thirds of NS3 is highly conserved amongst HCV isolates, with RNA-binding, RNA-stimulated NTPase, and RNA unwinding activities. Although NS4B and the NS5A phosphoprotein are also likely components of the replicase, their specific roles are unknown. The C-terminal polyprotein cleavage product, NS5B, is the elongation subunit of the HCV replicase possessing RNA-dependent RNA polymerase (RdRp) activity (Behrens, S. E.; Tomei, L.; DeFrancesco, R.; 1996; EMBO J. 15: 12-22*; and Lohmann, V.; Kxc3x6rner, F.; Herian, U.; Bartenschlager, R.; 1997; J. Virol. 71: 8416-8428*). It has been recently demonstrated that mutations destroying NS5B activity abolish infectivity of RNA in a chimp model (Kolykhalov, A. A.; Mihalik, K.; Feinstone, S. M.; Rice, C. M.; 2000; J. Virol. 74: 2046-2051*).
The development of new and specific anti-HCV treatments is a high priority, and virus-specific functions essential for replication are the most attractive targets for drug development. The absence of RNA dependent RNA polymerases in mammals, and the fact that this enzyme appears to be essential to viral replication, would suggest that the NS5B polymerase is an ideal target for anti-HCV therapeutics.
WO 00/06529 reports inhibitors of NS5B which are xcex1, xcex3-diketoacids.
WO 00/13708, WO 00/10573, and WO 00/18231 report inhibitors of NS5B proposed for treatment of HCV.
The present invention reduces the difficulties and disadvantages of the prior art by providing a novel class of compounds useful for the treatment and prevention of hepatitis C virus (HCV) infection. The aforesaid compounds have been found to inhibit an RNA dependent RNA polymerase encoded by HCV.
In a first aspect, the invention provides a compound of formula I: 
wherein:
X is CH or N;
Y is O or S;
Z is OH, NH2, NMeR3, NHR3; OR3 or 5- or 6-membered heterocycle, having 1 to 4 heteroatoms selected from O, N and S, said heterocycle being optionally substituted with from 1 to 4 substituents selected from:
COOH and xe2x80x94Oxe2x80x94(C6-10)aryl-(C2-6)alkenyl-COOH;
A is N, COR7 or CR5, wherein R5 is H, halogen, or (C1-6) alkyl and R7 is H or (C1-6 alkyl), with the proviso that X and A are not both N;
R6 is H, halogen, (C1-6 alkyl) or OR7, wherein R7 is H or (C1-6 alkyl);
R1 is selected from the group consisting of 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S,
phenyl, phenyl(C1-3)alkyl, (C2-6)alkenyl, phenyl(C2-6)alkenyl, (C3-6)cycloalkyl, (C1-6)alkyl, CF3, 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S,
wherein said heterocycle, phenyl, phenyl(C2-6)alkenyl and phenyl(C1-3)alkyl), alkenyl, cycloalkyl, (C1-6)alkyl, and heterobicycle are all optionally substituted with from 1 to 4 substituents selected from: OH, halogen, CF3, amino, cyano, phenyl(C1-4)alkoxy, COOH, xe2x80x94OCH2CONHCH2Ph, (C1-4)alkyl, xe2x80x94OCH2CONH(CH2)2-3N(CH3)2, (C1-4)alkoxy, xe2x80x94OCH2COxe2x80x94(morpholino), pyrrolidinyl, carboxy(C2-4)alkenyl, phenoxy, xe2x80x94NH(C2-4)acyl, xe2x80x94O(CH2)mOH, m being an integer from 2 to 4, SO3, and NO2;
R2 is selected from (C1-6)alkyl, (C3-7)cycloalkyl, (C1-3)cycloalkyl(C1-3)alkyl, ((C6-10)bicycloalkyl, norbornane, phenyl, and pyridyl, all of which is optionally substituted with from 1 to 4 substituents selected from
halogen, (C1-6)alkyl, xe2x80x94CH2OH, O-benzyl and OH;
R3 is selected from H, (C1-6)alkyl, (C3-6)cycloalkyl, (C3-6)cycloalkyl(C1-6)alkyl, (C6-10)aryl, (C6-10)aryl(C1-6)alkyl, (C2-6)alkenyl, (C3-6)cycloalkyl(C2-6)alkenyl, (C6-10)aryl(C2-6)alkenyl, N{(C1-6) alkyl}2, NHCOO(C1-6)alkyl(C6-10)aryl, NHCO(C6-10)aryl, (C1-6)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatoms selected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4 heteroatoms selected from O, N and S;
wherein said alkyl, cycloalkyl, aryl, alkenyl and heterocycle are all optionally substituted with from 1 to 4 substituents selected from:
OH, COOH, COO(C1-6)alkyl, (C1-6)alkyl, (C1-6)alkyl-hydroxy, phenyl, benzyloxy, halogen, (C2-4)alkenyl, (C2-4)alkenyl-(C1-6)alkyl-COOH, and carboxy(C2-4)alkenyl, 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N and S, said heterocycle being optionally substituted with from 1 to 4 substituents selected from:
(C1-6 alkyl), CF3, OH, (CH2)pCOOH, COOH, NHCH(C1-6alkyl)2, NHCO(C1-6 alkyl), NH2, NH(C1-6 alkyl), and N(C1-6 alkyl)2, wherein p is an integer from 1 to 4;
9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S, said heterobicycle being optionally substituted with from 1 to 4 substituents selected from:
halogen, OPO3H, sulfonamido, SO3H, SO2CH3, xe2x80x94CONH2, xe2x80x94COCH3, (C1-3)alkyl, (C2-4alkenyl)COOH, tetrazolyl, COOH, xe2x80x94CONH2, OH, NO2, NH2, xe2x80x94O(CH2)pCOOH, hydantoin, benzoyleneurea, triazolyl, (C1-4)alkoxy, cyano, azido, xe2x80x94Oxe2x80x94(C1-6)alkyl COOH, xe2x80x94Oxe2x80x94(C1-6)alkyl COOxe2x80x94(C1-6)alkyl, xe2x80x94NHCOCOOH, xe2x80x94NHCOCONHOH, xe2x80x94NHCOCONH2, xe2x80x94NHCOCONHCH3, xe2x80x94NHCO(C1-6)alkyl-COOH, xe2x80x94NHCOCONH(C1-6)alkyl-COOH, xe2x80x94NHCO(C3-7)cycloalkyl-COOH, xe2x80x94NHCONH(C6-10)aryl-COOH, xe2x80x94NHCONH(C6-10)aryl-COO(C1-6)alkyl, xe2x80x94NHCONH(C1-6)alkyl-COOH, xe2x80x94NHCONH(C1-6)alkyl-COO(C1-6)alkyl, xe2x80x94NHCONH(C1-6)alkyl-(C2-6)alkenyl-COOH, xe2x80x94NH(C1-6)alkyl-(C6-10)aryl-O(C1-6)alkyl COOH, xe2x80x94NH(C1-6)alkyl-(C6-10)aryl-COOH, xe2x80x94NHCH2COOH, xe2x80x94NHCONH2, xe2x80x94NHCO(C1-6)hydroxyalkyl COOH, xe2x80x94OCO(C1-6)hydroxyalkyl COOH, (C3-6)cycloalkyl COOH, 
xe2x80x83xe2x80x94NHCN, xe2x80x94NHCHO, xe2x80x94NHSO2CH3, and xe2x80x94NHSO2CF3;
6- or 10-membered aryl being optionally substituted with from 1 to 4 substituents selected from:
halogen, OPO3H, sulfonamido, SO3H, SO2CH3, nitro, xe2x80x94CONH2, xe2x80x94COCH3, (C1-3)alkyl, (C2-4alkenyl)COOH, tetrazolyl, COOH, xe2x80x94CONH2, OH, NH2, xe2x80x94O(CH2)pCOOH, hydantoin, benzoyleneurea, triazolyl, (C1-4)alkoxy, cyano, azido, xe2x80x94Oxe2x80x94(C1-6)alkyl COOH, xe2x80x94Oxe2x80x94(C1-6)alkyl COOxe2x80x94(C1-6)alkyl, xe2x80x94NHCOCOOH, xe2x80x94NHCOCONHOH, xe2x80x94NHCOCONH2, xe2x80x94NHCOCONHCH3, xe2x80x94NHCO(C1-6)alkyl-COOH, xe2x80x94NHCOCONH(C1-6)alkyl-COOH, xe2x80x94NHCO(C3-7)cycloalkyl-COOH, xe2x80x94NHCONH((C6-10)aryl-COOH, xe2x80x94NHCONH(C6-10)aryl-COO(C1-6)alkyl, xe2x80x94NHCONH(C1-6)alkyl-COOH, xe2x80x94NHCONH(C1-6)alkyl-COO(C1-6)alkyl, xe2x80x94NHCONH(C1-6)alkyl-(C2-6)alkenyl-COOH, xe2x80x94NH(C1-6)alkyl-(C6-10)aryl-O(C1-6)alkyl COOH, xe2x80x94NH(C1-6)alkyl-(C6-10)aryl-COOH, xe2x80x94NHCH2COOH, xe2x80x94NHCONH2, xe2x80x94NHCO(C1-6)hydroxyalkyl COOH, xe2x80x94OCO(C1-6)hydroxyalkyl COOH, (C3-6)cycloalkyl COOH, 
xe2x80x83xe2x80x94NHCN, xe2x80x94NHCHO, xe2x80x94NHSO2CH3, and xe2x80x94NHSO2CF3;
coumarin, (C1-6)alkyl-amino, di-(C1-6)alkyl-amino, C(halogen)3, xe2x80x94NH(C2-4)acyl, xe2x80x94NH((C6-10)aroyl, xe2x80x94CONHCH(CH2OH)2, xe2x80x94CO(C1-6)alkyl-COOH, xe2x80x94COxe2x80x94NH-alanyl, xe2x80x94(CH2)pCOOH, xe2x80x94OCH2Ph, xe2x80x94CONHbenzyl, xe2x80x94CONHpyridyl, xe2x80x94CONHCH2pyridyl, xe2x80x94CONH(C2-4)alkylN(C1-6alkyl)2, xe2x80x94CONH(C2-4) alkyl-morpholino, xe2x80x94CONH(C2-4) alkyl-pyrrolidino, xe2x80x94CONH(C2-4) alkyl-N-methylpyrrolidino, xe2x80x94CONH(C2-4) alkyl-(COOH)-imidazole, xe2x80x94CONHCH2CH(OH)CH2OH, xe2x80x94CONH(C1-6) alkyl-COOH, xe2x80x94CONH(C6-10) aryl-COOH, xe2x80x94CONH(C6-10) aryl-COO(C1-6) alkyl, xe2x80x94CONH(C1-6) alkyl-COO(C1-6) alkyl, xe2x80x94CONH(C6-10) aryl-(C1-6)alkyl-COOH,
xe2x80x94CONH(C6-10) aryl-(C2-6)alkenyl-COOH, xe2x80x94CONH(C2-6) alkylxe2x80x94CONH-9 or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N, and S, said heterobicycle being optionally substituted with from 1 to 4 substituents selected from;
COOH, (C6-10)aryl and (CH2)pCOOH, wherein p is an integer from 1 to 4;
xe2x80x94CONH(C6-10) aryl-5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N and S, said heterocycle being optionally substituted with from 1 to 4 substituents selected from:
COOH and (CH2)pCOOH, wherein p is an integer from 1 to 4;
xe2x80x94CONH(C1-6alkyl)CONH(C6-10aryl), said aryl being optionally substituted with from 1 to 4 substituents selected from:
COOH and (CH2)pCOOH, wherein p is an integer from 1 to 4;
xe2x80x94O(CH2)ptetrazolyl, wherein p is an integer from 1 to 4; and
n is zero or 1;
or a detectable derivative or salt thereof;
with the proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or hydroxyalkyl, then R1 is not a five membered heterocycle containing S and N;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R1 is (C2-10)alkyl, C3-10)alkenyl, (C3-6)cycloalkyl or phenyl, then R2 is not phenyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or hydroxyalkyl, then R1 is not 5-nitro-2-furyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is optionally substituted alkyl or cycloalkyl, then R1 is 5-aryl-2-furyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or cycloalkyl, then R1 is not 6-phenylbenzofuran-2-yl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is n-Pr, then R1 is not 2,3-benzofuranyl or phenyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is Me, then R1 is not phenyl or methoxy-2,3-benzofuranyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is Et, then R1 is not methoxy-2,3-benzofuranyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is (C1-8)alkyl, then R1 is not ethenyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is lower alkyl, then R1 is not substituted or unsubstituted phenyl, heteroaryl, CHCHphenyl, CHCHfuryl, CHCHpyridyl or CHCHquinolinyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is lower alkyl, cycloalkyl or hydroxyalkyl, then R1 is not alkenyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl, then R1 is not aryl, pyridyl, 2-hydroxyphenyl or alkenyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is (C1-4)alkyl or hydroxy(C1-4)alkyl, then R1 is not (C5-15)aryl, (C2-6)alkenyl or (C3-10)heteroarylene;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is (C1-12)alkyl, then R1 is not phenyl or aryl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or cycloalkyl, then R1 is not 2-hydroxyphenyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=1, then R1 is not methyl, ethyl or vinyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=1, then R1 is not 5-azabenzimidazol-2-yl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0 or 1, and R2 is (C1-4)alkyl or hydroxy(C1-4)alkyl then R1 is not C1-4alkyl optionally substituted by OH, COOH or halo;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0 or 1, R1 is heteroaryl or phenyl, then R2 is not heteroaryl or phenyl;
and with the further proviso that if X is CH, Y is O, Z is NHR3 wherein R3 is (C1-3)alkyl, substituted with COOH, COOalkyl or tetrazol-5-yl, and further substituted
with aryl or heteroaryl, n=0 or 1, and R1 is (C2-10)alkyl, (C3-6)cycloalkyl or phenyl, then R2 is not optionally substituted phenyl;
and with the further proviso that if X is CH, Y is O, Z is NMeR3 or NHR3 [wherein R3 is alkyl], n=0, and R2 is alkyl, cycloalkyl or aryl, then R1 is not a substituted 2-benzofuryl group;
and with the further proviso that if X is CH, Y is O, Z is NHR3 wherein R3 is alkyl, n=0, and R2 is alkyl or cycloalkyl, then R1 is not a substituted benzofuryl group or benzofuran-2-yl;
and with the further proviso that if X is CH, Y is O, Z is NHR3 wherein R3 is Me, n=0, and R2 is Me, then R1 is not methoxy-2,3-benzofuranyl;
and with the proviso that if X is CH, Y is O, Z is NHR3 [wherein R3 is alkyl or aryl], n=0, and R2 is alkyl not substituted with OH, then R1 is not aryl or heterocycle;
and with the further proviso that if X is CH, Y is O, Z is NHR3 [wherein R3 is alkyl, cycloalkyl, aryl or heteroaryl], n=0, and R2 is alkyl or cycloalkyl, then R1 is not aryl, heteroaryl or alkyl;
and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 or NMeR3 [wherein R3 is (C1-4)alkyl], n=0, and R2 is (C1-4)alkyl, then R1 is not phenyl bearing an N-substituted sulfonamido group;
and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is alkyl, cycloalkyl, aryl or heterocycle, n=0, and R2 is alkyl or cycloalkyl, then R1 is not 3,4-dialkoxyphenyl, 3,4-dialkoxyphenylphenylene or 3,4-dialkoxyphenylalkylene;
and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is H, alkyl, allyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl, n=0, and R2 is alkyl, cycloalkyl or hydroxyalkyl, then R1 is not tetrazolyl;
and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is alkyl, halogenoalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, arylsulphonyl, arylaminocarbonyl or arylmethylsulphonyl, n=0, and R2 is lower alkyl, then R1 is not substituted phenyl or heteroaryl;
and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is H, alkyl, phenyl or benzyl, n=0, and R2 is (C1-4)alkyl, then R1 is not phenyl;
and with the further proviso that if X is CH, Y is O, Z is OH or NH2, n=0, and R2 is alkyl or hydroxyalkyl, then R1 is not fluoroalkyl;
and with the further proviso that if X is CH, Y is O, Z is OH or NH2, n=0, and R2 is alkyl, then R1 is not alkenyl or aryl;
and with the further proviso that if X is CH, Y is O, Z is NHR3 [wherein R3 is thiazolyl], n=1, and R2 is (C1-8)alkyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, phenyl or heteroaryl, then R1 is not phenyl, phenyl(C2-4)alkenyl, heteroaryl, heterocycle, (C1-8)alkyl, (C2-6)alkenyl, or (C3-7)cycloalkyl;
and with the further proviso that if X is CH, Y is O, Z is OH or NH2, n=1, and R2 is (C1-5)alkyl, then R1 is not methyl or optionally halogenated phenyl;
and with the further proviso that if X is CH, Y is O, Z is NH2, n=0, and R2 is n-Pr, then R1 is not phenylethenyl;
and with the further proviso that if X is CH, Y is O, Z is NH2, n=0, and R2 is alkyl, then R1 is not substituted phenyl or naphthyl;
and with the further proviso that if X is CH, Y is O, Z is NH2 or NHR3 wherein R3 is (C1-4)alkyl, benzyl or p-fluorophenylmethyl, n=0, and R2is (C1-4)alkyl, then R1 is not phenyl substituted with acylamino.
Alternatively, the first aspect of the invention also provides a compound of formula Ia: 
wherein:
X is CH or N;
Y is O or S;
Z is OH, NH2, NMeR3 or NHR3;
and wherein
R1 is selected from 5- or 6-membered heteroaryl or heterocycle having 1 to 4 heteroatoms selected from O, N, and S,
phenyl, phenyl(C1-3)alkyl, (C2-6)alkenyl, phenyl(C2-6)alkenyl, (C3-6)cycloalkyl, (C1-6)alkyl, 9- or 10-atom heterobicycle having 1 to 4 heteroatoms selected from O, N and S,
wherein said heteroaryl, phenyl phenylalkenyl, phenylalkyl, alkenyl, cycloalkyl, (C1-6)alkyl, and heterobicycle are all optionally substituted with 1 to 4 substituents selected from: OH, halogen, cyano, phenyl(C1-4)alkoxy, COOH, xe2x80x94OCH2CONHCH2Ph, (C1-4)alkyl, xe2x80x94OCH2CONH(CH2)2-3N(CH3)2, (C1-4)alkoxy, xe2x80x94OCH2COxe2x80x94(morpholino), pyrrolidinyl, carboxy(C2-4)alkenyl, phenoxy, xe2x80x94NH(C2-4)acyl, xe2x80x94O(CH2)mOH, m being an integer from 2 to 4, SO3 and NO2;
R2 is selected from (C1-6)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl(C1-3)alkyl, (C6-10)bicycloalkyl, norbornane, phenyl, and pyridyl, all of which is optionally substituted with from 1 to 4 substituents selected from:
halogen, (C1-6)alkyl, xe2x80x94CH2OH, O-benzyl and OH;
R3 is selected from (C1-6)alkyl, (C3-6)cycloalkyl, (C3-6)cycloalkyl(C1-6)alkyl, (C6-10)aryl, (C6-10)aryl(C1-6)alkyl, (C2-6)alkenyl, (C3-6)cycloalkyl(C2-6)alkenyl, (C6-10)aryl(C2-6)alkenyl, and 5- to 10-membered heterocycle having 1 to 4 heteroatoms selected from O, N and S;
wherein said alkyl, cycloalkyl, aryl, alkenyl and heterocycle are all optionally substituted with from 1 to 4 substituents selected from:
OH, COOH, COO(C1-6)alkyl, (C1-6)alkyl, phenyl, benzyloxy, halogen, (C2-4)alkenyl, carboxy(C2-4)alkenyl, 5- to 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N and S, said heterocycle being optionally substituted with from 1 to four substituents selected from:
CH3, CF3, OH, CH2COOH and COOH;
9- to 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S said heterobicycle being optionally substituted with from 1 to 4 substituents selected from:
halogen, (C1-3)alkyl, (C1-3)alkoxy, tetrazolyl, COOH, xe2x80x94CONH2, triazolyl, OH, and xe2x80x94O(C1-3)alkylCOOH; (C1-4)alkoxy, cyano, amino, azido, (C1-6)alkyl-amino, di-(C1-6)alkyl-amino, OPO3H, sulfonamido, SO3H, SO2CH3, nitro, C(halo)3, xe2x80x94NH(C2-4)acyl,
xe2x80x94NHCOCOOH, xe2x80x94NHCH2COOH, xe2x80x94NHCONH2, 
xe2x80x83xe2x80x94NHCN, xe2x80x94NHCHO, xe2x80x94NHSO2CH3, xe2x80x94NHSO2CF3, xe2x80x94NH(C6-10)aroyl, xe2x80x94CONH2, xe2x80x94COxe2x80x94NH-alanyl, xe2x80x94(CH2)pCOOH, xe2x80x94OCH2Ph, xe2x80x94Oxe2x80x94(C1-6)alkyl COOH, xe2x80x94NHCO(C1-6)hydroxyalkyl COOH, xe2x80x94OCO(C1-6)hydroxyalkyl COOH, (C3-6)cycloalkyl COOH, xe2x80x94CONHbenzyl, xe2x80x94CONHpyridyl, xe2x80x94CONHCH2pyridyl, xe2x80x94CONH(C2-4)alkylN(CH3)2, xe2x80x94CONH(C2-4)alkylmorpholino and xe2x80x94O(CH2)ptetrazolyl, p being an integer from 1 to 4; and
n is zero or 1; or a salt thereof;
with the proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or hydroxyalkyl, then R1 is not a five membered heterocycle containing S and N;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R1 is (C2-10)alkyl, (C3-10)alkenyl, (C3-6)cycloalkyl or phenyl, then R2 is not phenyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or hydroxyalkyl, then R1 is not 5-nitro-2-furyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is optionally substituted alkyl or cycloalkyl, then R1 is 5-aryl-2-furyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or cycloalkyl, then R1 is not 6-phenylbenzofuran-2-yl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is n-Pr, then R1 is not 2,3-benzofuranyl or phenyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is Me, then R1 is not phenyl or methoxy-2,3-benzofuranyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is Et, then R1 is not methoxy-2,3-benzofuranyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2is (C1-8)alkyl, then R1 is not ethenyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is lower alkyl, then R1 is not substituted or unsubstituted phenyl, heteroaryl, CHCHphenyl, CHCHfuryl, CHCHpyridyl or CHCHquinolinyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is lower alkyl, cycloalkyl or hydroxyalkyl, then R1 is not alkenyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl, then R1 is not aryl, pyridyl, 2-hydroxyphenyl or alkenyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is (C1-4)alkyl or hydroxy(C1-4)alkyl, then R1 is not (C5-15)aryl, (C2-6)alkenyl or (C3-10)heteroarylene;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is (C1-12)alkyl, then R1 is not phenyl or aryl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or cycloalkyl, then R1 is not 2-hydroxyphenyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=1, then R1 is not methyl, ethyl or vinyl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=1, then R1 is not 5-azabenzimidazol-2-yl;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0 or 1, and R2 is (C1-4)alkyl or hydroxy(C1-4)alkyl then R1 is not C1-4alkyl optionally substituted by OH, COOH or halo;
and with the further proviso that if X is CH, Y is O, Z is OH, n=0 or 1, R1 is heteroaryl or phenyl, then R2 is not heteroaryl or phenyl;
and with the further proviso that if X is CH, Y is O, Z is NHR3 wherein R3 is (C1-3)alkyl, substituted with COOH, COOalkyl or tetrazol-5-yl, and further substituted with aryl or heteroaryl, n=0 or 1, and R1 is (C2-10)alkyl, (C3-6)cycloalkyl or phenyl, then R2 is not optionally substituted phenyl;
and with the further proviso that if X is CH, Y is O, Z is NMeR3 or NHR3 [wherein R3 is alkyl], n=0, and R2 is alkyl, cycloalkyl or aryl, then R1 is not a substituted 2-benzofuryl group;
and with the further proviso that if X is CH, Y is O, Z is NHR3 wherein R3 is alkyl, n=0, and R2 is alkyl or cycloalkyl, then R1 is not a substituted benzofuryl group or benzofuran-2-yl;
and with the further proviso that if X is CH, Y is O, Z is NHR3 wherein R3 is Me, n=0, and R2 is Me, then R1 is not methoxy-2,3-benzofuranyl;
and with the proviso that if X is CH, Y is O, Z is NHR3 [wherein R3 is alkyl or aryl], n=0, and R2 is alkyl not substituted with OH, then R1 is not aryl or heterocycle;
and with the further proviso that if X is CH, Y is O, Z is NHR3 [wherein R3 is alkyl, cycloalkyl, aryl or heteroaryl], n=0, and R2 is alkyl or cycloalkyl, then R1 is not aryl, heteroaryl or alkyl;
and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 or NMeR3 [wherein R3 is (C1-4)alkyl], n=0, and R2 is (C1-4)alkyl, then R1 is not phenyl bearing an N-substituted sulfonamido group;
and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is alkyl, cycloalkyl, aryl or heterocycle, n=0, and R2 is alkyl or cycloalkyl, then R1 is not 3,4-dialkoxyphenyl, 3,4-dialkoxyphenylphenylene or 3,4-dialkoxyphenylalkylene;
and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is H, alkyl, allyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl, n=0, and R2 is alkyl, cycloalkyl or hydroxyalkyl, then R1 is not tetrazolyl;
and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is alkyl, halogenoalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, arylsulphonyl, arylaminocarbonyl or arylmethylsulphonyl, n=0, and R2 is lower alkyl, then R1 is not substituted phenyl or heteroaryl;
and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is H, alkyl, phenyl or benzyl, n=0, and R2 is (C1-4)alkyl, then R1 is not phenyl;
and with the further proviso that if X is CH, Y is O, Z is OH or NH2, n=0, and R2 is alkyl or hydroxyalkyl, then R1 is not fluoroalkyl;
and with the further proviso that if X is CH, Y is O, Z is OH or NH2, n=0, and R2 is alkyl, then R1 is not alkenyl or aryl;
and with the further proviso that if X is CH, Y is O, Z is NHR3 [wherein R3 is thiazolyl], n=1, and R2 is (C1-8)alkyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, phenyl or heteroaryl, then R1 is not phenyl, phenyl(C2-4)alkenyl, heteroaryl, heterocycle, (C1-8)alkyl, (C2-6)alkenyl, or (C3-7)cycloalkyl;
and with the further proviso that if X is CH, Y is O, Z is OH or NH2, n=1, and R2 is (C1-5)alkyl, then R1 is not methyl or optionally halogenated phenyl;
and with the further proviso that if X is CH, Y is O, Z is NH2, n=0, and R2 is n-Pr, then R1 is not phenylethenyl;
and with the further proviso that if X is CH, Y is O, Z is NH2, n=0, and R2is alkyl, then R1 is not substituted phenyl or naphthyl;
and with the further proviso that if X is CH, Y is O, Z is NH2 or NHR3 wherein R3 is (C1-4)alkyl, benzyl or p-fluorophenylmethyl, n=0, and R2 is (C1-4)alkyl, then R1 is not phenyl substituted with acylamino.
In a second aspect, the invention provides an inhibitor of NS5B having the formula I, or Ia, without the provisos.
In a third aspect, the invention provides an inhibitor of HCV replication having the formula I, or Ia, without the provisos.
In a fourth aspect, the invention provides a method of treating or preventing HCV infection in a mammal, comprising administering to the mammal an effective amount of a compound of formula I, or Ia, without the provisos.
In a fifth aspect, the invention provides a pharmaceutical composition for the treatment or prevention of HCV infection, comprising an effective amount of a compound of formula I, or Ia, without the provisos, and a pharmaceutically acceptable carrier.
In a sixth aspect, the invention provides a use for the manufacture of a medicament of formula I, or Ia, without the provisos, for the treatment of HCV infection.
In a seventh aspect, the invention provides a use of a compound of formula I, or Ia, without the provisos, as an inhibitor of NS5B.
In an eighth aspect, the invention provides a use of a compound of formula I, or Ia, without the provisos, as an inhibitor of HCV replication.
In a ninth aspect, the invention provides a method of treating HCV infection in a mammal, comprising giving instructions to a third party to administer a compound of formula I, or Ia, without the provisos to a subject suffering from HCV infection.